The present invention relates to morpholine and thiomorpholine derivatives, pharmaceutical compositions, and methods of using such derivatives.
It is well established that there are two classes of receptors for the neurotransmitter .gamma.-aminobutyric acid (GABA), which have been identified as GABA.sub.A and GABA.sub.B. Selective GABA.sub.B agonists, such as (-)-baclofen, are known and have demonstrated clinical utility as muscle relaxants. Kerr, et al, in GABA.sub.B Receptors in Mammalian Function, Bowery, et al, eds., pp. 29-45, (Chichester 1990), have reported low affinity GABA.sub.B antagonists, such as phaclofen and 2-hydroxy saclofen. Olpe, et al, Eur. J. Pharmacol., 187, 27 (1990), discloses the GABA.sub.B antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348), which, although having a low receptor affinity (comparable to 2-hydroxy saclofen), can penetrate the blood/brain barrier. In addition, Hills, et al, Br. J. Pharmacol., 102, pp. 5-6 (1991) discloses phosphinic acid derivatives having activity as GABA.sub.B antagonists.
General absence (petit mal) seizures are a clinically and experimentally unique class of seizures, typically occuring in children. It has been reported that GABA.sub.B antagonists are effective in blocking the occurrence of petit mal seizures in a number of animal models: Snead III, Pharmacology Communications, 2 (1-2), pp. 63-69 (1992); Hosford, et al, Pharmacology Communications, 2 (1-2), pp. 123-124 (1992).
Mondadori, et al, Pharmacoloay Communications, 2 (1-2), pp. 93-97 (1992), disclose the use of GABA.sub.B receptor antagonists for improving cognitive performance in animal models.
Bowery, et al, Arzneim. -Forsch./Drug Res., 42 (I), Nr. 2a, pp. 215-223 (1992) relates to the physiological role of GABA.sub.B receptor antagonists.
Morpholine and thiomorpholine derivatives bearing substituents at the 2 position are known. Loftus, Syn. Comm., 10 (1), 59-73 (1980), discloses compounds of the formula ##STR2## wherein R is methyl or benzyl.
European Patent Publication EP 398426 discloses compounds of the formula ##STR3## wherein: X is O or S; P is C.sub.6 H.sub.5 --CH.sub.2 -- or C.sub.6 H.sub.5 --CH.sub.2 --O--C(O)--; R.sup.17 is C.sub.1 -C.sub.4 alkoxy or OH; W is a reactive leaving group, such as halogen or sulfonyloxy; and Het represents a heteroaryl group.
European Patent Publication EP 311948 discloses compounds of the formula ##STR4## wherein Z is a Cl, Br, I, --OSO.sub.2 CH.sub.3 or --OSO.sub.2 --C.sub.6 H.sub.4 --CH.sub.3.